The present invention relates to novel tricyclic sulfonamide compounds and their derivatives useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are inhibitors of matrix metalloproteinases, e.g., gelatinase A (MMP-2), collagenase-3 (MMP-13), and stromelysin-1 (MMP-3): More particularly, the novel compounds of the present invention are useful in the treatment of atherosclerotic plaque rupture, aortic aneurism, heart failure, left ventricular dilation, restenosis, periodontal disease, comeal ulceration, treatment of burns, decubital ulcers, wound repair, cancer, inflammation, pain, arthritis, osteoporosis, multiple sclerosis, renal disease, and other autoimmune or inflammatory disorders dependent on the tissue invasion of leukocytes or other activated migrating cells. Additionally, the compounds of the present invention are useful in the treatment of acute and chronic neurodegenerative disorders including stroke, head trauma. spinal cord injury, Alzheimer""s disease. amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson""s disease, Huntington""s disease, prion diseases, myasthenia gravis, and Duchenne""s muscular dystrophy.
Gelatinase A and stromelysin-1 are members of the matrix metalloproteinase (MMP) family (Woessner J. F., FASEB J., 1991;5:2145-2154). Other members include fibroblast collagenase, neutrophil collagenase, gelatinase B (92 kDa gelatinase), stromelysin-2, stromelysin-3, matrilysin, collagenase 3 (Freije J. M., Diez-ltza I., Balbin M., Sanchez L. M., Blasco R., Tolivia J., and Lopez-Otin C., J. Biol Chem., 1994;269:16766-16773), and the newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65).
The catalytic zinc in matrix metalloproteinases is a focal point for inhibitor design. The modification of substrates by introducing chelating groups has generated potent inhibitors such as peptide hydroxymates and thiol-containing peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation.
The ability of the matrix metalloproteinases to degrade various components of connective tissue makes them potential targets for controlling pathological processes. For example, the rupture of an atherosclerotic plaque is the most common event initiating coronary thrombosis. Destabilization and degradation of the extracellular matrix surrounding these plaques by MMPs has been proposed as a cause of plaque fissuring. The shoulders and regions of foam cell accumulation in human atherosclerotic plaques show locally increased expression of gelatinase B, stromelysin-l, and interstitial collagenase. In situ zymography of this tissue revealed increased gelatinolytic and caseinolytic activity (Galis Z. S., Sukhova G. K., Lark M. W., and Libby P., xe2x80x9cIncreased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques,xe2x80x9d J. Clin. Invest., 1994;94:2494-2503). In addition, high levels of stromelysin RNA message have been found to be localized to individual cells in atherosclerotic plaques removed from heart transplant patients at the time of surgery (Henney A. M., Wakeley P. R., Davies M. J., Foster K., Hembry R., Murphy G., and Humphries S., xe2x80x9cLocalization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization,xe2x80x9d Proc. Nat""l. Acad Sci., 1991;88:8154-8158).
Inhibitors of matrix metalloproteinases will have utility in treating degenerative aortic disease associated with thinning of the medial aortic wall. Increased levels of the proteolytic activities of MMPs have been identified in patients with aortic aneurisms and aortic stenosis (Vine N. and Powell J. T., xe2x80x9cMetalloproteinases in degenerative aortic diseases,xe2x80x9d Clin. Sci., 1991;81:233-239).
Heart failure arises from a number of diverse etiologies, but a common characteristic is cardiac dilation, which has been identified as an independent risk factor for mortality (Lee T. H., Hamilton M. A., Stevenson L. W., Moriguchi J. D., Fonarow G. C., Child J. S., Laks H., and Walden J. A., xe2x80x9cImpact of left ventricular size on the survival in advanced heart failure,xe2x80x9d Am. J. Cardiol., 1993;72:672-676).
This remodeling of the failing heart appears to involve the breakdown of extracellular matrix. Matrix metalloproteinases are increased in patients with both idiopathic and ischemic heart failure (Reddy H. K., Tyagi S. C., Tjaha I. E., Voelker D. J., Campbell S. E., and Weber K. T., xe2x80x9cActivated myocardial collagenase in idiopathic dilated cardiomyopathy,xe2x80x9d Clin. Res., 1993;41:660A; Tyagi S. C., Reddy H. K., Voelker D., Tjara I. E., and Weber K.T., xe2x80x9cMyocardial collagenase in failing human heart,xe2x80x9d Clin. Res., 1993;41:681A). Animal models of heart failure have shown that the induction of gelatinase is important in cardiac dilation (Armstrong P. W., Moe G. W., Howard R. J., Grima E. A., and Cruz T. F., xe2x80x9cStructural remodeling in heart failure: gelatinase induction,xe2x80x9d Can. J. Cardiol., 1994;10:214-220), and cardiac dilation precedes profound deficits in cardiac function (Sabbah H. N., Kono T., Stein P. D., Mancini G. B., and Goldstein S., xe2x80x9cLeft ventricular shape changes during the course of evolving heart failure,xe2x80x9d Am. J Physiol., 1992;263:H266-270).
Neointimal proliferation, leading to restenosis, frequently develops after coronary angioplasty. The migration of vascular smooth muscle cells (VSMCs) from the tunica media to the neointima is a key event in the development and progression of many vascular diseases and a highly predictable consequence of mechanical injury to the blood vessel (Bendeck M. P., Zempo N., Clowes A. W., Galardy R. E., and Reidy M., xe2x80x9cSmooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat,xe2x80x9d Circulation Research, 1994;75:539-545). Northern blotting and zymographic analyses indicated that gelatinase A was the principal MMP expressed and excreted by these cells. Further, antisera capable of selectively neutralizing gelatinase A activity also inhibited VSMC migration across basement membrane barrier. After injury to the vessel, gelatinase A activity increased more than 20-fold as VSMCs underwent the transition from a quiescent state to a proliferating, motile phenotype (Pauly R. R., Passaniti A., Bilato C., Monticone R., Cheng L., Papadopoulos N., Gluzband Y. A., Smith L., Weinstein C., Lakatta E., and Crow M. T., xe2x80x9cMigration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation,xe2x80x9d Circulation Research, 1994;75:41-54).
Collagenase and stromelysin activities have been demonstrated in fibroblasts isolated from inflamed gingiva (Ultto V.J., Applegren R., and Robinson P. J., xe2x80x9cCollagenase and neutral metalloproteinase activity in extracts from inflamed human gingiva,xe2x80x9d J. Periodontal Res., 1981; 16:417424), and enzyme levels have been correlated to the severity of gum disease (Overall C. M., Wiebkin O. W., and Thonard J. C., xe2x80x9cDemonstrations of tissue collagenase activity in vivo and its relationship to inflammation severity in human gingiva,xe2x80x9d J. Periodontal Res., 1987;22:81-88). Proteolytic degradation of extracellular matrix has been observed in corneal ulceration following alkali burns (Brown S. I., Weller C. A., and Wasserman H. E., xe2x80x9cCollagenolytic activity of alkali burned comeas,xe2x80x9d Arch. Ophthalmol., 1969;81:370-373). Thiol-containing peptides inhibit the collagenase isolated from alkali-burned rabbit comeas (Bums F. R., Stack M. S., Gray R. D., and Paterson C. A., Invest. Ophthalmol., 1989;30:1569-1575).
Stromelysin is produced by basal keratinocytes in a variety of chronic ulcers (Saarialho-Kere U. K., Ulpu K., Pentland A. P., Birkedal-Hansen H., Parks W. O., and Welgus H. G., xe2x80x9cDistinct Populations of Basal Keratinocytes Express Stromelysin-1 and Stromelysin-2 in Chronic Wounds.xe2x80x9d J. Clin. Invest, 1994;94:79-88).
Stromelysin-1 mRNA and protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of the proliferating epidermnis. Stromelysin-1 may thus prevent the epidermis from healing.
Davies et al., (Cancer Res., 1993;53:2087-2091) reported that a peptide hydroxymate, BB-94, decreased the tumor burden and prolonged the survival of mice bearing human ovarian carcinoma xenografts. A peptide of the conserved MMP propeptide sequence was a weak inhibitor of gelatinase A and inhibited human tumor cell invasion through a layer of reconstituted basement membrane (Melchiori A., Albili A., Ray J. M., and Stetler-Stevenson W. G., Cancer Res., 1992;52:2353-2356). The natural tissue inhibitor of metalloproteinase-2 (TIMP-2) also showed blockage of tumor cell invasion in in vitro models (DeClerck Y. A., Perez N., Shimada H., Boone T. C., Langley K. E., and Taylor S. M., Cancer Res., 1992;52:701-708). Studies of human cancers have shown that gelatinase A is activated on the invasive tumor cell surface (Strongin A. Y., Marmer B. L., Grant G. A., and Goldberg G. I., J. Biol. Chem., 1993;268:14033-14039) and is retained there through interaction with a receptor-like molecule (Monsky W. L., Kelly T., Lin C.-Y., Yeh Y., Stetler-Stevenson W. G., Mueller S. C., and Chen W.-T., Cancer Res., 1993;53:3159-3164).
Inhibitors of MMPs have shown activity in models of tumor angiogenesis (Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P., Scanziani E., Brown P.D., and Giavazzi R., Journal of the National Cancer Institute, 1995;87:293 and Benelli R., Adatia R., Ensoli B., Stetler-Stevenson W. G., Santi L., and Albini A, Oncology Research, 1994;6:251-257).
Several investigators have demonstrated consistent elevation of stromelysin and collagenase in synovial fluids from osteo- and rheumatoid arthritis patients as compared to controls (Walakovits L. A., Moore V. L., Bhardwaj N., Gallick G. S., and Lark M. W., xe2x80x9cDetection of stromelysin and collagenase in synovial fluid from patients with rheumatoid arthritis and post-traumatic knee injury,xe2x80x9d Arthritis Rheum., 1992;35:35-42; Zafarullah M., Pelletier J. P., Cloutier J. M., and Marcel-Pelletier J., xe2x80x9cElevated metalloproteinases and tissue inhibitor of metalloproteinase mRNA in human osteoarthritic synovia.xe2x80x9d J Rheumatol., 1993;20:693-697). TIMP-1 and TIMP-2 prevented the formation of collagen fragments, but not proteoglycan fragments in both the bovine nasal and pig articular cartilage models for arthritis, while a synthetic peptide hydroxamate could prevent the formation of both fragments (Andrews H. J., Plumpton T. A., Harper G. P., and Cawston T. E., Agents Actions, 1992;37:147-154; Ellis A. J., Curry V. A., Powell E. K., and Cawston T. E., Biochem. Biophys. Res. Commun., 1994;201:94-101).
Gijbels et al., (J. Clin. Invest., 1994;94:2177-2182) recently described a peptide hydroxamate, GM6001, that suppressed the development or reversed the clinical expression of experimental autoimmune encephalomyelitis (EAE) in a dose dependent manner, suggesting the use of MMP inhibitors in the treatment of autoimmune inflammatory disorders such as multiple sclerosis.
A recent study by Madri has elucidated the role of gelatinase A in the extravasation of T-cells from the blood stream during inflammation (Ramanic A. M., and Madri J. A., xe2x80x9cThe Induction of 72-kDa Gelatinase in T Cells upon Adhesion to Endothelial Cells is VCAM-1 Dependent,xe2x80x9d J. Cell Biology, 1994;125:1165-1178). This transmigration past the endothelial cell layer is coordinated with the induction of gelatinase A and is mediated by binding to the vascular cell adhesion molecule-1 (VCAM-1). Once the barrier is compromised, edema and inflammation are produced in the CNS. Also, leukocytic migration across the blood-brain barrier is known to be associated with the inflammatory response in EAE. Inhibition of the metalloproteinase gelatinase A would block the degradation of extracellular matrix by activated T-cells that is necessary for CNS penetration.
These studies provide the basis for the expectation that an effective inhibitor of gelatinase A and/or stromelysin-1 would have value in the treatment of diseases involving disruption of extracellular matrix resulting in inflammation due to lymphocytic infiltration, inappropriate migration of metastatic or activated cells, or loss of structural integrity necessary for organ function.
Neuroinflammatory mechanisms are implicated in a broad range of acute and chronic neurodegenerative disorders, including stroke, head trauma, multiple sclerosis, and Alzheimer""s disease, to name a few (McGeer E. G. and McGeer P. L., xe2x80x9cNeurodegeneration and the immune systemxe2x80x9d. In: Calne D. B., ed. Neurodegenerative Diseases, W. B. Saunders, 1994:277-300). Other disorders that may involve neuroinflammatory mechanisms include amyotrophic lateral sclerosis (Leigh P. N., xe2x80x9cPathogenic mechanisms in amyotrophic lateral sclerosis and other motor neuron disordersxe2x80x9d. In: Calne D. B., ed., Neurodegenerative Diseases, W. B. Saunders, 1994:473-88), cerebral amyloid angiopathy (Mandybur T. I. and Balko G., xe2x80x9cCerebral amyloid angiopathy with granulomatous angiitis ameliorated by steroid-cytoxan treatment,xe2x80x9d Clin. Neuropharm., 1992;1 5:241-7), AIDS (Gendelman H. E. and Tardieu M., xe2x80x9cMacrophages/microglia and the pathophysiology of CNS injuries in AIDS,xe2x80x9d J. Leukocyte Biol., 1994;56:387-8), Parkinson""s disease, Huntington""s disease, prion diseases, and certain disorders involving the peripheral nervous system, such as myasthenia gravis and Duchenne""s muscular dystrophy. Neuroinflammation, which occurs in response to brain injury or autoimmune disorders, has been shown to cause destruction of healthy tissue (Martin R., MacFarland H. F., and McFarlin D. E., xe2x80x9cImmunological aspects of demyelinating diseases,xe2x80x9d Annul Rev. Immunol, 1992;10:153-87; Clark R. K., Lee E. V., Fish C. J., et al., xe2x80x9cDevelopment of tissue damage, inflammation and resolution following stroke: an immunohistochemical and quantitative planimetric study,xe2x80x9d Brain Res. Bull., 1993;31:565-72; Giulian D. and Vaca K., xe2x80x9cInflammatory glia mediate delayed neuronal damage after ischemia in the central nervous system,xe2x80x9d Stroke, 1993;24(Suppl 12): 184-90; Patterson P. H., xe2x80x9cCytokines in Alzheimer""s disease and multiple sclerosis,xe2x80x9d Cur. Opinion Neurobiol, 1995;5:642-6; McGeer P. L., Rogers J., and McGeer E. G., xe2x80x9cNeuroimmune mechanisms in Alzheimer disease pathogenesis,xe2x80x9d Alzheimer Dis. Assoc. Disorders, 1994;8:149-58; Martin R. and McFarland H. F., xe2x80x9cImmunological aspects of experimental allergic encephalomyelitis and multiple sclerosis.xe2x80x9d Crit. Rev. Clin. Lab. Sci., 1995;32:121-82; Rogers J., Webster S., Lue L. F., et al., xe2x80x9cInflammation and Alzheimer""s disease pathogenesisxe2x80x9d. In: Neurobiology of Aging, 1996;17:681-686; Rothwell N. J. and Relton J. K., xe2x80x9cInvolvement of cytokines in acute neurodegeneration in the CNS,xe2x80x9d Neurosci. Biobehav. Rev., 1993; 17:217-27). The pathological profiles and clinical courses of these disorders differ widely, but they all have in common the participation of immune/inflammatory elements in the disease process. In particular, many neurodegenerative disorders are characterized by large numbers of reactive microglia in postmortem brain samples, indicative of an active inflammatory process (McGeer E. G. and McGeer P. L., supra., 1994).
Increasing attention is being directed toward inflammatory mechanisms in Alzheimer""s disease. Several lines of evidence support the involvement of neuroinflammation in Alzheimer""s disease: 1) There is a significant increase in inflammatory markers in the Alzheimer brain, including acute phase reactants, cytokines, complement proteins, and MHC molecules (McGeer et al., supra., 1994; Rogers et al., supra.); 2) There is evidence that xcex2-amyloid induces neurodegenerative changes primarily through interactions with inflammatory molecules, and that inflammation alone is sufficient to induce neurodegeneration (Rogers et al., supra); and 3) Growing epidemiological data indicate that anti-inflammatory therapy can delay the onset and slow the progression of Alzheimer""s disease (McGeer P. L. and Rogers J., xe2x80x9cAnti-inflammatory agents as a therapeutic approach to Alzheimer""s disease,xe2x80x9d Neurology, 1992;42:447-9; Canadian Study of Health and Aging, xe2x80x9cRisk factors for Alzheimer""s disease in Canada,xe2x80x9d Neurology, 1994;44:2073-80; Lucca U., Tettamanti M., Forloni G., and Spagnoli A., xe2x80x9cNonsteroidal antiinflammatory drug use in Alzheimer""s disease,xe2x80x9d Biol. Psychiatry, 1994;36:854-66; Hampel H. and Mxc3xcller N., xe2x80x9cInflammatory and immunological mechanisms in Alzheimer""s disease,xe2x80x9d DNandP, 1995;8:599-608; Breitner J. C. S., Gau B. A., Welsh K. A., et al., xe2x80x9cInverse association of anti-inflammatory treatments and Alzheimer""s disease: Initial results of a co-twin control study,xe2x80x9d Neurology, 1994;44:227-32; Breitner J. C. S., Welsh K. A., Helms M. J., et al., xe2x80x9cDelayed onset of Alzheimer""s disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs,xe2x80x9d Neurobiol. Aging, 1995;16:523-30; Andersen K., Launer L. J., Ott A., Hoes A. W., Breteler M. M. B., and Hofman A., xe2x80x9cDo nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer""s disease? The Rotterdam Study,xe2x80x9d Neurology, 1995;45:1xe2x80x94;1-5; Rich J. B., Rasmusson D. X., Folstein M. F., et al., xe2x80x9cNonsteroidal anti-inflammatory drugs in Alzheimer""s disease,xe2x80x9d Neurology, 1995;45:51-5; Aisen P. S., xe2x80x9cAnti-inflammatory therapy for Alzheimer""s disease.xe2x80x9d Dementia, 1995;9:173-82; Rogers et al., supra). Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), most commonly for the treatment of rheumatoid arthritis, decreases the probability of developing Alzheimer""s disease, and there is reason to believe that other anti-inflammatory agents may also be effective, although direct evidence for the efficacy of such treatments is lacking (Hamper and Mxc3xcller, supra., 1995). Furthermore, virtually all of the currently available compounds, which include corticosteroids, NSAIDs, antimalarial drugs, and colchicine, have serious drawbacks that make them undesirable in the treatment of chronic disorders. Glucocorticoids, which are in wide clinical use as anti-inflammatory/immunosuppressive drugs, can be directly neurotoxic and also are toxic to systemic organs at moderate to high doses. NSAIDs have gastrointestinal and renal side effects that obviate long-term use in most people, and few of them cross the blood-brain barrier in significant amounts. The toxic properties of chloroquine compounds and colchicine also are well known. An anti-inflammatory drug that is well-tolerated by patients and that crosses the blood-brain barrier has significant advantages for the treatment of acute and chronic degenerative diseases of the central nervous system.
Normal kidney function is dependent on the maintenance of tissues constructed from differentiated and highly specialized renal cells which are in a dynamic balance with their surrounding extracellular matrix (ECM) components (Davies M. et al., xe2x80x9cProteinases and glomerular matrix turnover,xe2x80x9d Kidney Int., 1992;41:671-678). Effective glomerular filtration requires that a semi-permeable glomerular basement membrane (GBM) composed of collagens, fibronectin, enactin, laminin and proteoglycans is maintained. A structural equilibrium is achieved by balancing the continued deposition of ECM proteins with their degradation by specific metalloproteinases (MMP). The MMP belong to a supergene family of zinc endopeptidases (Woessner J. F., xe2x80x9cMatrix metalloproteinases and their inhibitors in connective tissue remodelling,xe2x80x9d FASEB J., 1991;5:2145-2154). These proteins are first secreted as proenzymes and are subsequently activated in the extracellular space. These proteinases are in turn subject to counter balancing regulation of their activity by naturally occurring inhibitors referred to as TIMPs (tissue inhibitors of metalloproteinases).
Deficiency or defects in any component of the filtration barrier may have catastrophic consequences for longer term renal function. For example, in hereditary nephritis of Alport""s type, associated with mutations in genes encoding ECM proteins, defects in collagen assembly lead to progressive renal failure associated with splitting of the GBM and eventual glomerular and interstitial fibrosis. By contrast in inflammatory renal diseases such as glomerulonephritis, cellular proliferation of components of the glomerulus often precede obvious ultrastructural alteration of the ECM matrix. Cytokines and growth factors implicated in proliferative glomerulonephritis such as interleukin-1, tumor necrosis factor, and transforming growth factor beta can upregulate metalloproteinase expression in renal mesangial cells (Martin J. et al., xe2x80x9cEnhancement of glomerular mesangial cell neutral proteinase secretion by macrophages: role of interleukin 1,xe2x80x9d J. Immunol., 1986;137:525-529; Marti H. P. et al., xe2x80x9cHomology cloning of rat 72 kDa type IV collagenase: Cytokine and second-messenger inducibility in mesangial cells,xe2x80x9d Biochem. J., 1993;291:441-446; Marti H. P. et al., xe2x80x9cTransforming growth factor-b stimulates glomerular mesangial cell synthesis of the 72 kDa type IV collagenase,xe2x80x9d Am. J. Pathol., 1994;144:82-94). These metalloproteinases are believed to be intimately involved in the aberrant tissue remodeling and cell proliferation characteristic of renal diseases, such as, IgA nephropathy which can progress to through a process of gradual glomerular fibrosis and loss of functional GBM to end-stage renal disease. Metalloproteinase expression has already been well-characterized in experimental immune complex-mediated glomerulonephritis such as the anti-Thy 1.1 rat model (Bagchus W. M., Hoedemaeker P. J., Rozing J., Bakker W. W., xe2x80x9cGlomerulonephritis induced by monoclonal anti-Thy 1.1 antibodies: A sequential histological and ultrastructural study in the rat,xe2x80x9d Lab. Invest., 1986;55:680-687; Lovett D. H., Johnson R. J., Marti H. P., Martin J., Davies M., Couser W. G., xe2x80x9cStructural characterization of the mesangial cell type IV collagenase and enhanced expression in a model of immune complex mediated glomerulonephritis,xe2x80x9d Am. J. Pathol, 1992;141:85-98).
Unfortunately, at present, there are very limited therapeutic strategies for modifying the course of progressive renal disease. Although many renal diseases have an inflammatory component, their responses to standard immunosuppressive regimes are unpredictable and potentially hazardous to individual patients. The secondary consequences of gradual nephron failure such as activation of the reninangiotensin system, accompanied by individual nephron glomerular hyperfiltration and renal hypertension, may be effectively treated with ACE inhibitors or angiotensin II receptor antagonists; but at best, these compounds can only reduce the rate of GFR decline.
A novel strategy to treat at least some renal diseases has been suggested by recent observations of MMP behavior. A rat mesangial cell MMP has been cloned (MMP-2) which is regulated in a tissue specific manner, and in contrast to other cellular sources such as tumor cell lines, is induced by cytokines (Brown P. D., Levy A. T., Margulies I., Liotta L. A., Stetler-Stevenson W. G., xe2x80x9cIndependent expression and cellular processing of Mr 72,000 type IV collagenase and interstitial collagenase in human tumorigenic cell lines,xe2x80x9d Cancer Res., 1990;50:6184-6191; Marti H. P. et al., xe2x80x9cHomology cloning of rat 72 kDa type IV collagenase: Cytokine and second-messenger inducibility in mesangial cells,xe2x80x9d Biochem. J., 1993;291:441446). While MMP-2 can specifically degrade surrounding ECM, it also affects the phenotype of adjacent mesangial cells. Inhibition of MMP-2 by antisense oligonucleotides or transfection techniques can induce a reversion of the proliferative phenotype of cultured mesangial cells to a quiescent or non-proliferative phenotype mimicking the natural in vitro behavior of these cells (Kitamura M. et al., xe2x80x9cGene transfer of metalloproteinase transin induces aberrant behaviour of cultured mesangial cells,xe2x80x9d Kidney Int., 1994;45:1580-1586; Turck J. et al., xe2x80x9cMatrix metalloproteinase 2 (gelatinase A) regulates glomerular mesangial cell proliferation and differentiation,xe2x80x9d J. Biol. Chem., 1996;271:15074-15083).
Inhibitors of MMP (MMPi) clearly have potential clinical applications in a host of diseases characterized by disturbance of extracellular matrix-cell interactions resulting in abnormal tissue remodeling (Vincenti M. P. et al., xe2x80x9cUsing inhibitors of metalloproteinases to treat arthritis,xe2x80x9d Arthritis Rheum., 1994;8:1115-1126; Grams F. et al., xe2x80x9cX-ray structures of human neutrophil collagenase complexed with peptide hydroxyamate and peptide thiol inhibitors. Implications for substrate binding and rational drug design,xe2x80x9d Eur. J. Biochem., 1995;228:830-841).
We have identified a series of tricyclic sulfonamide compounds and their derivatives that are inhibitors of matrix metalloproteinases, particularly collagenase-3, stromelysin-1 and gelatinase A, and thus useful as agents for the treatment of multiple sclerosis, atherosclerotic plaque rupture, restenosis. aortic aneurism, heart failure, left ventricular dilation, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound repair, cancer, inflammation, pain, arthritis, osteoporosis, renal disease, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes or other activated migrating cells, acute and chronic neurodegenerative disorders including stroke, head trauma, spinal cord injury, Alzheimer""s disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson""s disease, Huntington""s diseases, prion diseases, myasthenic gravis, and Duchenne""s muscular dystrophy.
Accordingly, a first aspect of the present invention is a compound of Formula I 
wherein n is zero or an integer of 1 or 2;
X is xe2x80x94Oxe2x80x94,
xe2x80x94S(O)pxe2x88x92 wherein p is zero or an integer of 1 or 2, 
wherein R2 is hydrogen, alkyl, acyl, or benzyl, xe2x80x94CH2xe2x80x94, or 
xe2x80x83R is hydrogen,
alkyl,
hydroxyalkyl,
alkoxyalkyl,
trifluoromethyl,
alkanoyloxyalkyl,
alkanoyl aminoalkyl,
alkylthioalkyl,
alkylsulfinylalkyl,
alkylsulfonylalkyl,
arninoalkyl,
alkylaminoalkyl,
dialkylaminoalkyl,
N-alkylpiperazinoalkyl,
N-phenylalkylpiperazinoalkyl,
morpholinoalkyl,
thiomorpholinoalkyl,
piperidinoalkyl,
pyrrolidinoalkyl,
N-alkylalkylpiperidinolalkyl,
pyridylalkyl,
thienylalkyl,
quinolinylalkyl,
thiazolylalkyl,
cycloalkyl,
cycloalkylalkyl,
phenyl,
phenyl substituted by one to three substituents selected from the group consisting of:
hydroxy,
alkoxy,
alkyl,
alkylthio,
alkylsulfinyl,
alkylsulfonyl,
amino,
alkylamino,
dialkylamino,
halogen,
cyano,
nitro,
trifluoromethyl or on adjacent carbon atoms by either a one to two carbon alkenylenedioxy group or a two to three carbon alkenyleneoxy group,
phenylalkyl,
phenylalkyl wherein phenyl is substituted by alkyl,
alkoxy,
halogen, or
trifluoromethyl,
heteroaryl,
heteroaryl substituted by one to two substituents selected from the group consisting of:
alkyl, or
halogen,
biphenyl,
biphenyl substituted by alkyl,
alkoxy,
halogen,
trifluoromethyl, or
cyano,
biphenylalkyl or
biphenylalkyl wherein biphenyl is substituted by
alkyl,
alkoxy,
halogen,
trifluoromethyl, or
cyano;
D is zero or an integer of I to 3;
L is zero or an integer of I to 3;
R1 is hydrogen,
a side chain of a natural amino acid or
a side chain of an unnatural amino acid;
Y is OR3 wherein R3 is hydrogen,
methyl,
ethyl, or
benzyl, or
NHxe2x80x94OR4 wherein R4 is hydrogen,
alkyl, or
benzyl;
and corresponding isomers thereof, or a pharmaceutically acceptable salt thereof.
As matrix metalloproteinase inhibitors, the compounds of Formula I are useful as agents for the treatment of multiple sclerosis. They are also useful as agents for the treatment of atherosclerotic plaque rupture, aortic aneurism, heart failure, left ventricular dilation, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound repair, cancer metastasis, tumor angiogenesis, inflammation, pain, arthritis, osteoporosis, renal disease, and other autoimmune or inflammatory disorders dependent upon tissue invasion by leukocytes or other activated migrating cells, acute and chronic neurodegenerative disorders including stroke, head trauma, spinal cord injury, Alzheimer""s disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson""s disease, Huntington""s disease, prion diseases, myasthenia gravis, and Duchenne""s muscular dystrophy.
A still further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of a compound of Formula I in unit dosage form in the treatment methods mentioned above. Finally, the present invention is directed to methods for production of compounds of Formula I.